CA2877724A1 - Racecadotril liquid compositions - Google Patents
Racecadotril liquid compositions Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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Abstract
A liquid composition comprising racecadotril and cyclodextrin.
Description
RACECADOTRIL LIQUID COMPOSITIONS
BACKGROUND OF THE INVENTION
Field of the Invention [0001] The present invention relates to liquid compositions. More particularly, the present invention relates to liquid compositions containing racecadotril and the method of making said compositions.
Related Background Art [0002] Diarrhea is an intestinal disorder that is characterized by an increase in the frequency of watery bowel movements. It may result from a variety of causes including bacteria or viral induced diarrhea. Food intolerance caused by allergy or the consumption of foods such as fatty or spicy foods may result in diarrhea. Food poisoning may also lead to diarrhea. In some instances, diarrhea may be a symptom of other conditions and diseases.
BACKGROUND OF THE INVENTION
Field of the Invention [0001] The present invention relates to liquid compositions. More particularly, the present invention relates to liquid compositions containing racecadotril and the method of making said compositions.
Related Background Art [0002] Diarrhea is an intestinal disorder that is characterized by an increase in the frequency of watery bowel movements. It may result from a variety of causes including bacteria or viral induced diarrhea. Food intolerance caused by allergy or the consumption of foods such as fatty or spicy foods may result in diarrhea. Food poisoning may also lead to diarrhea. In some instances, diarrhea may be a symptom of other conditions and diseases.
[0003] Diarrhea is symptomatic of an intestinal or other bodily function disorder. Various prescription and nonprescription products can be taken for relief. However, many of these products provide relief with some side effects.
[0004] Racecadotril is also used in the treatment of diarrhea. It reduces (i) hypersecretion of water and electrolytes into the intestinal lumen, (ii) the incidence and duration of acute diarrhea and (iii) diarrhea-associated symptoms.
[0005] Presently, racecadotril is available in solid oral dosage forms.
SUBSTITUTE SHEET (RULE 26) SUMMARY OF THE INVENTION
SUBSTITUTE SHEET (RULE 26) SUMMARY OF THE INVENTION
[0006] The present invention is directed to a liquid composition comprising racecadotril and cyclodextrin.
[0007] In one embodiment, the inventive composition comprises about 0.01 wt.%
to about 24.0 wt.% racecadotril and about 1 wt.% to about 95 wt.% of a cyclodextrin, wherein each wt.% is based upon 100 ml of the composition.
to about 24.0 wt.% racecadotril and about 1 wt.% to about 95 wt.% of a cyclodextrin, wherein each wt.% is based upon 100 ml of the composition.
[0008] The present invention also includes a method for treating a subject experiencing diarrhea comprising the step of orally administering to the subject a composition comprising racecadotril and cyclodextrin.
DETAILED DESCRIPTION OF THE INVENTION
DETAILED DESCRIPTION OF THE INVENTION
[0009] As used herein, "stable" refers to a liquid composition substantially free of chemical degradation of racecadotril or substantial color change. In one embodiment, the total chemical degradant products of racecadotril should be less than 0.2 percent by weight (wt.%), e.g. less than 0.1 wt.% based on the total wt.% of racecadotril when stored at 3 months and 40 C. In another embodiment, the total chemical degradant products of racecadotril should be less than 0.2 percent by weight (wt.%), e.g. less than 0.1 wt.% based on the total wt.%
of racecadotril when stored at 6 months and 40 C.
of racecadotril when stored at 6 months and 40 C.
[0010] The percent degradation products are determined by calculating the %
peak area of the degradation product peak areas relative to the peak areas of the Racecadotril peaks in the HPLC
chromatograms. In one embodiment, the total chemical degradant products of racecadotril should be less than 0.5 % of racecadotril, e.g., less than 0.2 % based on of the total % of racecadotril when stored at 3 months and 40 C.
peak area of the degradation product peak areas relative to the peak areas of the Racecadotril peaks in the HPLC
chromatograms. In one embodiment, the total chemical degradant products of racecadotril should be less than 0.5 % of racecadotril, e.g., less than 0.2 % based on of the total % of racecadotril when stored at 3 months and 40 C.
[0011] The present invention is a liquid composition comprising racecadotril and cyclodextrin.
[0012] Racecadotril's efficacy in reducing the symptoms of diarrhea have been demonstrated in various studies. One of the benefits of using racecadotril over other remedies is that in SUBSTITUTE SHEET (RULE 26) comparative trials racecadotril was shown to have fewer adverse events such as post-treatment constipation.
[0013] In the present invention, the racecadotril is included in a stable liquid composition.
[0014] Racecadotril is a compound with low water solubility, making it difficult to formulate into liquid compositions. However, oral liquid compositions are the most preferred dosage form for administering medications to the pediatric population.
[0015] In one embodiment, a RS racemic form of racecadotril is used. In another embodiment, a R form of racecadotril is used.
[0016] Racecadotril is included in the liquid composition in an amount from about 0.01 grams to about 0.5 grams per 100 ml of the liquid composition. Preferably, the racecadotril is about 0.05 grams to about 0.4 grams, and more preferably, about 0.1 grams to about 0.3 grams per 100 ml of the liquid composition. In one embodiment, the racecadotril is about 0.25 grams per 100 ml of liquid composition.
[0017] In one embodiment, the viscosity of the liquid composition is from about 1 to about 500 centipoise at room temperature (25 C) measured using a Brookfield Viscometer.
[0018] The pH of the liquid composition is from about 1 to about 6.
Preferably, the pH is about 3 to about 5. More preferably, the pH is about 4.5.
Preferably, the pH is about 3 to about 5. More preferably, the pH is about 4.5.
[0019] In one embodiment, a buffering system may be included to maintain the pH at the value or in the desired range. The buffer may be a citrate, an acetate, a phosphate, or mixtures thereof.
Preferably, an acetate buffer is used.
Preferably, an acetate buffer is used.
[0020] In one embodiment the racecadotril is dissolved into the liquid composition.
[0021] Cyclodextrins are compounds used in a wide variety of products, which include pharmaceutical, food, consumer and chemical products. They are synthesized from starch via an enzymatic reaction.
[0022] Suitable cyclodextrins include, for example, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, or mixtures thereof.
[0023] In one embodiment, the cyclodextrin is hydroxypropyl-beta-cyclodextrin.
One source of hydroxypropyl-beta-cyclodextrin is CAVASOL W7 available from International Speciality Products Corporation (ISP).
SUBSTITUTE SHEET (RULE 26) [0024] In another embodiment, the cyclodextrin is a sulfobutyl ether derivative of 0-cyclodextrin, sold under the tradename CAPTISOL available from Captisol.
One source of hydroxypropyl-beta-cyclodextrin is CAVASOL W7 available from International Speciality Products Corporation (ISP).
SUBSTITUTE SHEET (RULE 26) [0024] In another embodiment, the cyclodextrin is a sulfobutyl ether derivative of 0-cyclodextrin, sold under the tradename CAPTISOL available from Captisol.
[0025] The cyclodextrin is included in the composition in an amount from about 1 grams to about 70 grams per 100 ml of the liquid composition. Preferably, the cyclodextrin is about 5 grams to about 60 grams, and more preferably, about 5 grams to about 50 grams per 100 ml of the liquid composition.
[0026] In one embodiment, the cyclodextrin is from about 40 grams to about 60 grams per 100 ml of the liquid composition.
[0027] In another embodiment, the cyclodextrin is from about 15 grams to about 30 grams per 100 ml of the liquid composition.
[0028] The liquid composition also has water. Water is the solvent that fills the gap after all other components have been added. The amount of water that is included varies because the water is added to bring the composition up to a desired volume amount.
[0029] Optionally, a variety of ingredients may be included in the liquid composition of the present invention.
[0030] For example, propylene glycol may be included in the liquid composition. Propylene glycol has many uses, such as for example a moisturizer in food and medicines, and as a solvent for food colorings and flavorings. It is a colorless, nearly odorless, clear, viscous liquid with a faintly sweet taste, hygroscopic and miscible with water, acetone, and chloroform.
[0031] Any coloring agent suitable for use in a food or pharmaceutical product may be used in the present inventive composition. Typical coloring agents include, for example, azo dyes, quinopthalone dyes, triphenylmethane dyes, xanthene dyes, indigoid dyes, iron oxides, iron hydroxides, titanium dioxide, natural dyes, and mixtures thereof. More specifically, suitable colorants include, but are not limited to patent blue V, acid brilliant green BS, red 2G, azorubine, ponceau 4R, amaranth, D&C red 33, D&C red 22, D&C red 26, D&C red 28, D&C
yellow 10, FD&C yellow 5, FD&C yellow 6, FD&C red 3, FD&C red 40, FD&C blue 1, FD&C blue 2, FD&C green 3, brilliant black BN, carbon black, iron oxide black, iron oxide red, iron oxide yellow, titanium dioxide, riboflavin, carotenes, antyhocyanines, turmeric, cochineal extract, clorophyllin, canthaxanthin, caramel, betanin, and mixtures thereof.
SUBSTITUTE SHEET (RULE 26) [0032] Similarly, a flavor may be included in the liquid composition. The amount of flavor added to the composition will be dependent upon the desired taste characteristics.
yellow 10, FD&C yellow 5, FD&C yellow 6, FD&C red 3, FD&C red 40, FD&C blue 1, FD&C blue 2, FD&C green 3, brilliant black BN, carbon black, iron oxide black, iron oxide red, iron oxide yellow, titanium dioxide, riboflavin, carotenes, antyhocyanines, turmeric, cochineal extract, clorophyllin, canthaxanthin, caramel, betanin, and mixtures thereof.
SUBSTITUTE SHEET (RULE 26) [0032] Similarly, a flavor may be included in the liquid composition. The amount of flavor added to the composition will be dependent upon the desired taste characteristics.
[0033] The composition may contain other ingredients or components, such as aromas;
sweeteners such as, sorbitol, high fructose corn syrup, sugar, and high intensity sweeteners such as sucralose, aspartame and saccharine and the like; viscosity modifiers such as xanthan gum;
preservatives such as sodium benzoate NF, buffers such as citric acid and/or sodium chloride;
surfactants such as polysorbate 80 and/or sodium lauryl sulfate or mixtures thereof [0034] In one embodiment, the inventive liquid composition includes about 0.1 wt.% to about 0.3 wt.% racecadotril and about 40 wt.% to about 65 wt.% cyclodextrin, wherein each wt.% is based upon 100 ml of the composition.
sweeteners such as, sorbitol, high fructose corn syrup, sugar, and high intensity sweeteners such as sucralose, aspartame and saccharine and the like; viscosity modifiers such as xanthan gum;
preservatives such as sodium benzoate NF, buffers such as citric acid and/or sodium chloride;
surfactants such as polysorbate 80 and/or sodium lauryl sulfate or mixtures thereof [0034] In one embodiment, the inventive liquid composition includes about 0.1 wt.% to about 0.3 wt.% racecadotril and about 40 wt.% to about 65 wt.% cyclodextrin, wherein each wt.% is based upon 100 ml of the composition.
[0035] In another embodiment, the inventive liquid composition includes about 0.1 wt.% to about 0.3 wt.% racecadotril and about 10 wt.% to about 40 wt.% cyclodextrin, wherein each wt.% is based upon 100 ml of the composition.
[0036] The solubility of the racecadotril in the inventive composition is about 1.5 to about 4.0 mg/ml.
[0037] The liquid composition of the present invention may be made by any method known to those skilled in the art so long as it results in the desired composition.
[0038] Suitable methods include, for example, combining each ingredient in a mixing kettle, where the ingredients may be added sequentially or in any manner so long as the intended result is achieved. Moreover, the mixing action should be sufficient to incorporate each ingredient into the composition.
[0039] In one embodiment the liquid of the present invention comprises a second active ingredient. The second active ingredient may be, for example, present in a suspended state, or may be solubilized in the liquid composition. In one embodiment, the second active ingredient is a digestive health active ingredient may be, for example, laxatives, antacids, proton pump inhibitors, anti-gas agents, antiemetics, H2 blockers, a second antidiarrheal agent, and the like.
In one embodiment, the second active ingredient is microencapsulated.
In one embodiment, the second active ingredient is microencapsulated.
[0040] Suitable anti-gas agents include but are not limited to simethicone.
[0041] Suitable additional antidiarrheal agents include but are not limited to loperamide.
SUBSTITUTE SHEET (RULE 26) [0042] The inventive liquid composition may be delivered in any suitable delivery system. For example, in one embodiment, the liquid composition is delivered orally. In another embodiment, the composition is a liquid oral dosage form. In still another embodiment, a soft shell solid dosage form is used to deliver the liquid composition. In still yet another embodiment, a hard shell solid dosage form is used to deliver the liquid composition. In still yet another embodiment, a tablet dosage form is used to deliver the liquid composition.
SUBSTITUTE SHEET (RULE 26) [0042] The inventive liquid composition may be delivered in any suitable delivery system. For example, in one embodiment, the liquid composition is delivered orally. In another embodiment, the composition is a liquid oral dosage form. In still another embodiment, a soft shell solid dosage form is used to deliver the liquid composition. In still yet another embodiment, a hard shell solid dosage form is used to deliver the liquid composition. In still yet another embodiment, a tablet dosage form is used to deliver the liquid composition.
[0043] The present invention also includes a method for treating a subject experiencing diarrhea comprising the step of orally administering to the subject a composition comprising racecadotril and cyclodextrin.
[0044] The following example is provided to further illustrate the compositions and methods of the present invention. It should be understood that the present invention is not limited to the examples described.
RACECADOTRIL ORAL LIQUID FORMULATION
RACECADOTRIL ORAL LIQUID FORMULATION
[0045] The composition for an oral racecadotril liquid is shown in Table 1.
Utilizing the materials in Table 1, the following mixing steps were used:
Utilizing the materials in Table 1, the following mixing steps were used:
[0046] Step 1: A solution of was formed by mixing the purified water and hydroxypropyl beta-cyclodextrin in a suitable vessel with a laboratory mixer.
[0047] Step 2: The racecadotril was added to the solution in Step 1 and mixed in a laboratory shaker for at least 12 hours and a clear solution was formed.
[0048] Step 3: The citric acid, sorbitol solution, high fructose corn syrup, and sodium chloride was mixed to form a solution and mixed using a laboratory mixer until dissolved.
[0049] Step 4: A separate mixture was prepared by mixing the flavor into the polyethylene glycol 400 in a suitable vessel. This mixture was then mixed with the solution from Step 3 and diluted to volume with purified water.
SUBSTITUTE SHEET (RULE 26) [0050] Table 1: Racecadotril Oral Liquid Composition (2.5 mg/g) Ingredient % Weight by Weight Racecadotril 0.25 Hydroxypropyl beta-cyclodextrinl 7.00 Citric Acid 0.21 Sorbitol (70% weight/weight) 17.50 High Fructose Corn Syrup (42% weight/weight) 49.75 Sodium Chloride 0.25 Polyethylene Glycol 400 0.50 Flavor 0.10 Purified Water 24.44 Total 100.0*
1: Commercially available from the ISP as CAVASOL W7 EXAMPLE 2: Concentrated Racecadotril Aqueous composition Three formulations of racecadotril in an aqueous buffer of acetate were prepared and three formulations of racecadotril in an aqueous buffer of citrate were prepared.
These formulations were prepared utilizing a mixture of racecadotril in the Sulfobutyl ether derivative of13-cyclodextrin (Captisol0) and are shown in Table 2.
Table 2: Racecadotril Sulfobutyl Ether Derivative of I3-cyclodextrin Based Aqueous Compositions SUBSTITUTE SHEET (RULE 26) Solvent System Actual Composition Racecadotril Acetate Racecad-Captisol Acetate by Assay Captisol Acetate Captisol Buffer otril Lot # (w/v) Buffer (mL) (mg/mL) (g) Buffer (mL) (w/w /0) (w/w /0) (wily%) Formula 1 60% 100 2.62 59.9972 54.0 52.49 47.25 0.26 Formula 3 70% 100 2.41 70.0018 48.0 59.18 40.58 0.24 Formula 5 78% 100 2.26 80.0035 54.6 59.30 40.47 0.23 Solvent System Actual Composition Actual Racecadotril Citrate Racecad-Captisol Citrate by Assay Captisol Citrate Captisol Buffer otril Lot # (w/v) Buffer (mg/mL) (g) Buffer (mL) (w/w%) (w/w /0) (w/w /0) Formula 2 60% 100 2.43 60.0120 66.0 47.51 52.25 0.24 Formula 4 69% 100 2.39 70.0016 62.0 52.90 46.86 0.24 Formula 6 80% 50 1.92 39.9954 33.0 54.69 45.12 0.19 Utilizing the materials in TABLE 2, the following mixing steps were taken to form the solutions.
Step 1: In a suitable glass bottle, the Captisol were weighed, mixed and prepared as 60%, 70%
and 78% in pH 4.5 acetate buffers, respectively (Formulae 1, 3 and 5). Also, the Captisol were weighed and prepared as 60%, 69% and 80% in pH 4.5 citrate buffers, respectively (Formulae 2, 4 and 6).
Step 2: The pH of each bottle was adjusted to pH 4.5 with either glacial acetic acid (17.4 M) or citric acid (3 M).
Step 3: The Racecadotril was slowly added to each bottle in Step 2, utilizing the vortex mixer to mix for 5 minutes, and then placed each bottle into a laboratory shaker and mixed for 24 hours until a solution was formed.
Stability of Racecadotril in Aqueous Solutions For comparative purposes, the stability of racecadotril was tested at room temperature and at 40 C.
SUBSTITUTE SHEET (RULE 26) Table 3: Stability of Racecadotril in Water Time Racecadotril (%) in Racecadotril (%) in Water at Room Water at 40 C
Temperature (%) Initial 74.88 78.88 12 Hours 44.9 N/A
1 Week 1.0 0 2 Weeks 0.0 0.2 3 Weeks N/A N/A
These results show that at room temperature and at 40 C conditions, racecadotril is unstable after 12 hours. Moreover, at 1 week, racecadotril is present at less than 1%.
Stability of Racecadotril in Buffer Solutions For comparative purposes, the stability of racecadotril was analyzed when solubilized in pH 4.5 Acetate buffer and pH 4.5 Citrate buffer (Table 4).
Table 4: Stability of Racecadotril in Buffer Time Racecadotril in pH 4.5 Racecadotril in pH 4.5 Acetate Buffer at 40 C (% Citrate Buffer at 40 C
Racecadotril) (% Racecadotril) Initial 99.86 99.74 12 Hours 99.69 99.63 1 Week 96.7 95.3 2 Weeks 93.3 91.2 3 Weeks 91.5 89.0 4 Weeks 88.0 85.4 SUBSTITUTE SHEET (RULE 26) The data shows at 40 C and 4 weeks that although the stability is somewhat compromised, it is more stable in a buffer than in water. The data also demonstrates that racecadotril is more soluble in buffer than in water.
Stability of Racecadotril in Beta-Hydroxypropyl-Cyclodextrin (Beta-HPCD) Formulations of racecadotril in beta-hydroxypropyl-cyclodextrin were evaluated (Table 5).
Table 5: Stability of Racecadotril in Beta-Hydroxypropyl-Cyclodextrin (Beta-HPCD) Time Racecadotril in Racecadotril in Racecadotril in Racecadotril in Beta-HPCD at 40 C Beta-HPCD at 40 C Beta-HPCD at Beta-HPCD at (% ) without pH (% ) with pH 40 C (% ) without 40 C (% ) with pH
Adjustment, Adjustment to 4.5, pH Adjustment, Adjustment to Acetate Buffer Acetate Buffer Citrate Buffer 4.5, Citrate Buffer Initial 99.5 99.58 99.3 99.58 12 Hours 96.9 98.07 96.9 98.12 1 Week 94.1 96.16 93.6 96.20 2 Weeks 92.7 92.91 3 Weeks 88.95 89.59 4 Weeks 85.84 86.80 The data shows that the stability is similar to that in buffers alone, but higher solubility was achieved utilizing the Beta-HPCD.
Stability of Racecadotril in Sulfobutyl Ether Derivative of 13-cyclodextrini Solution SUBSTITUTE SHEET (RULE 26) The stability of samples prepared above in Example 2 utilizing Sulfobutyl ether derivative of 0-cyclodextrin (Captisol0) solutions was analyzed. The data is shown in Table 6.
TABLE 6: Stability Data of Racecadotril in Sulfobutyl Ether Derivative ofp-cyclodextrin based Aqueous Solution (3 month (k 40 C) Formula Formula Formula Formula Formula Formula Racecadotril (%) 90.95 89.23 91.32 91.28 92.54 92.64 Thiorphan (%) 0.08 0.13 0.07 0.09 0.06 0.05 Benzyl Alcohol (%) 1.3 1.29 1.3 1.11 1.22 0.87 Impurity C (%) 1.68 1.41 1.68 1.24 1.59 0.94 Impurity G (%) 0.96 7.42 1.14 5.73 1.33 4.93 Solubility (mg/mL) 2.62 2.43 2.41 2.39 2.26 1.92 Formula 1 - Captisol 60%w/w in pH 4.5 Acetate Buffer 2 - Captisol 60%w/w in pH 4.5 Citrate Buffer 3 - Captisol 70%w/w in pH 4.5 Acetate Buffer 4 - Captisol 69%w/w in pH 4.5 Citrate Buffer - Captisol 78%w/w in pH 4.5 Acetate Buffer 6 - Captisol 80%w/w in pH 4.5 Citrate Buffer Test Methods Sample preparation:
1. Pipet 1 mL of Racecadotril solution into a 100mL volumetric flask (V.F.) 2. Dilute to volume with the same buffer used in the solution preparation.
3. Further dilute the sample solution to about 0.1 mg1mL if necessary.
Sample Analysis Inject standards (0.1 mg/mL of Racecadotril in Acetonitrile) and samples onto a suitable HPLC system under conditions similar to those suggested below. Parameters may be modified to optimize chromatography.
The assay of Racecadotril is determined by using the external standard injected. The degradation products levels are determined by % peak area relative to the Racecadotril peak.
Chromatnraphic conditions (European Pharmacopoeia Racecadotril method): ______ Column: Phenomenex Luna 5 um C18 (2), 100A; 250 mm x 4.6 mm ID
(Column ID in EP is 4.0 mm) Column heater: 30 C
SUBSTITUTE SHEET (RULE 26) Wavelength: 210 nm lnj. Vol.: 104 Flow rate: 1 mL/min Gradient Table:
Time (min) flow %A %B
Initial 1.0 60 40 1.0 60 40 25 1.0 20 80 35 1.0 20 80 36 1.0 60 40 45 1.0 60 40 Mobil Phase A: Phosphate buffer, pH 2.5 (Buffer prep: dissolve lg of potassium dihydrogen phosphate in water, adjust to pH 2.5 with phosphoric acid, dilute to 1000mL
with water) Mobil Phase B: 100% Acetonitrile Stability of Racecadotril in Beta-Hydroxypropyl-Cyclodextrin (Beta-HPCD) ...............................................................................
.....................................................................
sommEgmoitAcm:momoommomoxoBeirAitampoxomm pH 3.6_ pH 4.0_ pH 4,5õ
Initial 99.93 100 99.68 0 0 0.02 1 week 97.21 97.01 96.33 0.69 0.7 0.022 2 week 94.88 95.02 92.61 1.4 1.39 0.4 3 week 93.01 92.23 89.29 2.13 2.09 0.59 a) 4 week 90.15 89.5 86.5 2.84 2.84 0.79 4g, g 6 week 85.75 83.98 80.25 4.33 4.28 1.14 8 week 80.68 78.53 75.06 5.78 5.37 1.51 ...............................................................................
.....................................................................
...............................................................................
.........................................................
Time pH 3.6 pH 4.O pH:4.5 pH 3.6 pH:4.:0 pH
4.5 . .
Initial 99.91 100 99.71 0 0 0.02 _ 1 week 96.45 95.93 96.44 0.79 0.89 0.22 2 week 92.01 93.19 93.19 1.72 1.41 0.4 _ 3 week 88.22 89.81 90.2 2.59 2.36 0.59 _ 4 week 84.51 86.78 87.41 3.38 2.79 0.79 _ 6 week 77.91 80.7 82.05 5.09 4.19 1.14 8 week 71.51 75.46 77.34 6.64 5.54 1.51 SUBSTITUTE SHEET (RULE 26) IIIIIIIIIIIIIIIIIIIIIIIIIIIItigill6IHIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
IIIIIIIIIIIIIIIIIIIIIIIlliiiillkiltIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
IIIIIIIIIIIIIIIIIIEIIIiikilliIllbilliIll .................................. .....
...............................................................................
...............................................................................
....................................
p1-130 : pH 4.0 :iõ pH 4.5 i:i pH 3A:: ,r pH 4.0 f pH 4.4i pH 3.q:: t pH 4.0 4: pH 4.4 !!
0 0 0.01 0 I 0 I 0.02 0.07 I 0 I 0.21 -0 0 0.02 0.93 0.93 0.21 1.17 1.36 3.17 tifi -0.11 0.07 0.04 1.87 1.82 0.4 1.74 1.7 6.5 (cs _ +-, cu 0.14 0.19 0.06 2.78 2.83 0.58 1.93 2.66 9.43 ::(...) 0.3 0.38 0.11 3.56 3.52 0.72 3 3.62 11.84 -0.57 0.71 0.2 5.17 5.16 1.04 3.82 5.67 17.32 1 1.19 0.36 6.33 6.2 1.25 5.28 8.46 21.73 ::::::::::::::::::::::::::::::::::::::::::::::::::...x.:::::::::::::::::::.:.::
:.:::::::::::...::::::::::::::::::::::::::::::::::::::::::::::::.:.x.x.:.x.x.x.
x.x.x.:x.x.:.x...:x.x.:.x.xx.:::.:.x.xx.....:.x.x.:.x.x.x.x.:.x.xx.x.:.:.
:::::::::::::::::::::dra.P!,i,%1:tVe::::::::::M MMENNIMOWAVONEMM:
...............................................................................
...............................................................................
.........................................
...............................................................................
...............................................................................
...............................................
, pH 3.6 pH 4.0 pH 4.5 , p1-13.6 , pH 4.0 pH 4.5 pH 3.6 pH 4.0 pH 4.5: i!
0.01 0 0 0.01 0.09 0 1 0.19 :: .. .. 0 0 0.01 0.98 1.23 0.18 1.78 1.95 3.15 !i!i:i :!=!!! -:.?zu::: 0.13 0.11 0.03 2.3 1.82 0.36 3.81 3.47 6.04 co 0.31 0.21 0.06 3.36 2.82 0.52 5.52 4.79 8.66 L.
v 0.47 0.4 0.1 4.23 3.43 0.62 7.38 6.57 11.16 _ 1.11 0.85 0.17 6.13 4.98 0.9 9.72 9.24 15.86 _ 1.8 1.42 0.29 7.54 6.22 1.11 12.47 11.26 19.95 _ [0051] While the invention has been described above with reference to specific embodiments thereof, it is apparent that many changes, modifications, and variations can be made without departing from the inventive concept disclosed herein. Accordingly, it is intended to embrace all such changes, modifications, and variations that fall within the spirit and broad scope of the appended claims. All patent applications, patents, and other publications cited herein are incorporated by reference in their entirety.
SUBSTITUTE SHEET (RULE 26)
SUBSTITUTE SHEET (RULE 26) [0050] Table 1: Racecadotril Oral Liquid Composition (2.5 mg/g) Ingredient % Weight by Weight Racecadotril 0.25 Hydroxypropyl beta-cyclodextrinl 7.00 Citric Acid 0.21 Sorbitol (70% weight/weight) 17.50 High Fructose Corn Syrup (42% weight/weight) 49.75 Sodium Chloride 0.25 Polyethylene Glycol 400 0.50 Flavor 0.10 Purified Water 24.44 Total 100.0*
1: Commercially available from the ISP as CAVASOL W7 EXAMPLE 2: Concentrated Racecadotril Aqueous composition Three formulations of racecadotril in an aqueous buffer of acetate were prepared and three formulations of racecadotril in an aqueous buffer of citrate were prepared.
These formulations were prepared utilizing a mixture of racecadotril in the Sulfobutyl ether derivative of13-cyclodextrin (Captisol0) and are shown in Table 2.
Table 2: Racecadotril Sulfobutyl Ether Derivative of I3-cyclodextrin Based Aqueous Compositions SUBSTITUTE SHEET (RULE 26) Solvent System Actual Composition Racecadotril Acetate Racecad-Captisol Acetate by Assay Captisol Acetate Captisol Buffer otril Lot # (w/v) Buffer (mL) (mg/mL) (g) Buffer (mL) (w/w /0) (w/w /0) (wily%) Formula 1 60% 100 2.62 59.9972 54.0 52.49 47.25 0.26 Formula 3 70% 100 2.41 70.0018 48.0 59.18 40.58 0.24 Formula 5 78% 100 2.26 80.0035 54.6 59.30 40.47 0.23 Solvent System Actual Composition Actual Racecadotril Citrate Racecad-Captisol Citrate by Assay Captisol Citrate Captisol Buffer otril Lot # (w/v) Buffer (mg/mL) (g) Buffer (mL) (w/w%) (w/w /0) (w/w /0) Formula 2 60% 100 2.43 60.0120 66.0 47.51 52.25 0.24 Formula 4 69% 100 2.39 70.0016 62.0 52.90 46.86 0.24 Formula 6 80% 50 1.92 39.9954 33.0 54.69 45.12 0.19 Utilizing the materials in TABLE 2, the following mixing steps were taken to form the solutions.
Step 1: In a suitable glass bottle, the Captisol were weighed, mixed and prepared as 60%, 70%
and 78% in pH 4.5 acetate buffers, respectively (Formulae 1, 3 and 5). Also, the Captisol were weighed and prepared as 60%, 69% and 80% in pH 4.5 citrate buffers, respectively (Formulae 2, 4 and 6).
Step 2: The pH of each bottle was adjusted to pH 4.5 with either glacial acetic acid (17.4 M) or citric acid (3 M).
Step 3: The Racecadotril was slowly added to each bottle in Step 2, utilizing the vortex mixer to mix for 5 minutes, and then placed each bottle into a laboratory shaker and mixed for 24 hours until a solution was formed.
Stability of Racecadotril in Aqueous Solutions For comparative purposes, the stability of racecadotril was tested at room temperature and at 40 C.
SUBSTITUTE SHEET (RULE 26) Table 3: Stability of Racecadotril in Water Time Racecadotril (%) in Racecadotril (%) in Water at Room Water at 40 C
Temperature (%) Initial 74.88 78.88 12 Hours 44.9 N/A
1 Week 1.0 0 2 Weeks 0.0 0.2 3 Weeks N/A N/A
These results show that at room temperature and at 40 C conditions, racecadotril is unstable after 12 hours. Moreover, at 1 week, racecadotril is present at less than 1%.
Stability of Racecadotril in Buffer Solutions For comparative purposes, the stability of racecadotril was analyzed when solubilized in pH 4.5 Acetate buffer and pH 4.5 Citrate buffer (Table 4).
Table 4: Stability of Racecadotril in Buffer Time Racecadotril in pH 4.5 Racecadotril in pH 4.5 Acetate Buffer at 40 C (% Citrate Buffer at 40 C
Racecadotril) (% Racecadotril) Initial 99.86 99.74 12 Hours 99.69 99.63 1 Week 96.7 95.3 2 Weeks 93.3 91.2 3 Weeks 91.5 89.0 4 Weeks 88.0 85.4 SUBSTITUTE SHEET (RULE 26) The data shows at 40 C and 4 weeks that although the stability is somewhat compromised, it is more stable in a buffer than in water. The data also demonstrates that racecadotril is more soluble in buffer than in water.
Stability of Racecadotril in Beta-Hydroxypropyl-Cyclodextrin (Beta-HPCD) Formulations of racecadotril in beta-hydroxypropyl-cyclodextrin were evaluated (Table 5).
Table 5: Stability of Racecadotril in Beta-Hydroxypropyl-Cyclodextrin (Beta-HPCD) Time Racecadotril in Racecadotril in Racecadotril in Racecadotril in Beta-HPCD at 40 C Beta-HPCD at 40 C Beta-HPCD at Beta-HPCD at (% ) without pH (% ) with pH 40 C (% ) without 40 C (% ) with pH
Adjustment, Adjustment to 4.5, pH Adjustment, Adjustment to Acetate Buffer Acetate Buffer Citrate Buffer 4.5, Citrate Buffer Initial 99.5 99.58 99.3 99.58 12 Hours 96.9 98.07 96.9 98.12 1 Week 94.1 96.16 93.6 96.20 2 Weeks 92.7 92.91 3 Weeks 88.95 89.59 4 Weeks 85.84 86.80 The data shows that the stability is similar to that in buffers alone, but higher solubility was achieved utilizing the Beta-HPCD.
Stability of Racecadotril in Sulfobutyl Ether Derivative of 13-cyclodextrini Solution SUBSTITUTE SHEET (RULE 26) The stability of samples prepared above in Example 2 utilizing Sulfobutyl ether derivative of 0-cyclodextrin (Captisol0) solutions was analyzed. The data is shown in Table 6.
TABLE 6: Stability Data of Racecadotril in Sulfobutyl Ether Derivative ofp-cyclodextrin based Aqueous Solution (3 month (k 40 C) Formula Formula Formula Formula Formula Formula Racecadotril (%) 90.95 89.23 91.32 91.28 92.54 92.64 Thiorphan (%) 0.08 0.13 0.07 0.09 0.06 0.05 Benzyl Alcohol (%) 1.3 1.29 1.3 1.11 1.22 0.87 Impurity C (%) 1.68 1.41 1.68 1.24 1.59 0.94 Impurity G (%) 0.96 7.42 1.14 5.73 1.33 4.93 Solubility (mg/mL) 2.62 2.43 2.41 2.39 2.26 1.92 Formula 1 - Captisol 60%w/w in pH 4.5 Acetate Buffer 2 - Captisol 60%w/w in pH 4.5 Citrate Buffer 3 - Captisol 70%w/w in pH 4.5 Acetate Buffer 4 - Captisol 69%w/w in pH 4.5 Citrate Buffer - Captisol 78%w/w in pH 4.5 Acetate Buffer 6 - Captisol 80%w/w in pH 4.5 Citrate Buffer Test Methods Sample preparation:
1. Pipet 1 mL of Racecadotril solution into a 100mL volumetric flask (V.F.) 2. Dilute to volume with the same buffer used in the solution preparation.
3. Further dilute the sample solution to about 0.1 mg1mL if necessary.
Sample Analysis Inject standards (0.1 mg/mL of Racecadotril in Acetonitrile) and samples onto a suitable HPLC system under conditions similar to those suggested below. Parameters may be modified to optimize chromatography.
The assay of Racecadotril is determined by using the external standard injected. The degradation products levels are determined by % peak area relative to the Racecadotril peak.
Chromatnraphic conditions (European Pharmacopoeia Racecadotril method): ______ Column: Phenomenex Luna 5 um C18 (2), 100A; 250 mm x 4.6 mm ID
(Column ID in EP is 4.0 mm) Column heater: 30 C
SUBSTITUTE SHEET (RULE 26) Wavelength: 210 nm lnj. Vol.: 104 Flow rate: 1 mL/min Gradient Table:
Time (min) flow %A %B
Initial 1.0 60 40 1.0 60 40 25 1.0 20 80 35 1.0 20 80 36 1.0 60 40 45 1.0 60 40 Mobil Phase A: Phosphate buffer, pH 2.5 (Buffer prep: dissolve lg of potassium dihydrogen phosphate in water, adjust to pH 2.5 with phosphoric acid, dilute to 1000mL
with water) Mobil Phase B: 100% Acetonitrile Stability of Racecadotril in Beta-Hydroxypropyl-Cyclodextrin (Beta-HPCD) ...............................................................................
.....................................................................
sommEgmoitAcm:momoommomoxoBeirAitampoxomm pH 3.6_ pH 4.0_ pH 4,5õ
Initial 99.93 100 99.68 0 0 0.02 1 week 97.21 97.01 96.33 0.69 0.7 0.022 2 week 94.88 95.02 92.61 1.4 1.39 0.4 3 week 93.01 92.23 89.29 2.13 2.09 0.59 a) 4 week 90.15 89.5 86.5 2.84 2.84 0.79 4g, g 6 week 85.75 83.98 80.25 4.33 4.28 1.14 8 week 80.68 78.53 75.06 5.78 5.37 1.51 ...............................................................................
.....................................................................
...............................................................................
.........................................................
Time pH 3.6 pH 4.O pH:4.5 pH 3.6 pH:4.:0 pH
4.5 . .
Initial 99.91 100 99.71 0 0 0.02 _ 1 week 96.45 95.93 96.44 0.79 0.89 0.22 2 week 92.01 93.19 93.19 1.72 1.41 0.4 _ 3 week 88.22 89.81 90.2 2.59 2.36 0.59 _ 4 week 84.51 86.78 87.41 3.38 2.79 0.79 _ 6 week 77.91 80.7 82.05 5.09 4.19 1.14 8 week 71.51 75.46 77.34 6.64 5.54 1.51 SUBSTITUTE SHEET (RULE 26) IIIIIIIIIIIIIIIIIIIIIIIIIIIItigill6IHIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
IIIIIIIIIIIIIIIIIIIIIIIlliiiillkiltIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
IIIIIIIIIIIIIIIIIIEIIIiikilliIllbilliIll .................................. .....
...............................................................................
...............................................................................
....................................
p1-130 : pH 4.0 :iõ pH 4.5 i:i pH 3A:: ,r pH 4.0 f pH 4.4i pH 3.q:: t pH 4.0 4: pH 4.4 !!
0 0 0.01 0 I 0 I 0.02 0.07 I 0 I 0.21 -0 0 0.02 0.93 0.93 0.21 1.17 1.36 3.17 tifi -0.11 0.07 0.04 1.87 1.82 0.4 1.74 1.7 6.5 (cs _ +-, cu 0.14 0.19 0.06 2.78 2.83 0.58 1.93 2.66 9.43 ::(...) 0.3 0.38 0.11 3.56 3.52 0.72 3 3.62 11.84 -0.57 0.71 0.2 5.17 5.16 1.04 3.82 5.67 17.32 1 1.19 0.36 6.33 6.2 1.25 5.28 8.46 21.73 ::::::::::::::::::::::::::::::::::::::::::::::::::...x.:::::::::::::::::::.:.::
:.:::::::::::...::::::::::::::::::::::::::::::::::::::::::::::::.:.x.x.:.x.x.x.
x.x.x.:x.x.:.x...:x.x.:.x.xx.:::.:.x.xx.....:.x.x.:.x.x.x.x.:.x.xx.x.:.:.
:::::::::::::::::::::dra.P!,i,%1:tVe::::::::::M MMENNIMOWAVONEMM:
...............................................................................
...............................................................................
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...............................................................................
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, pH 3.6 pH 4.0 pH 4.5 , p1-13.6 , pH 4.0 pH 4.5 pH 3.6 pH 4.0 pH 4.5: i!
0.01 0 0 0.01 0.09 0 1 0.19 :: .. .. 0 0 0.01 0.98 1.23 0.18 1.78 1.95 3.15 !i!i:i :!=!!! -:.?zu::: 0.13 0.11 0.03 2.3 1.82 0.36 3.81 3.47 6.04 co 0.31 0.21 0.06 3.36 2.82 0.52 5.52 4.79 8.66 L.
v 0.47 0.4 0.1 4.23 3.43 0.62 7.38 6.57 11.16 _ 1.11 0.85 0.17 6.13 4.98 0.9 9.72 9.24 15.86 _ 1.8 1.42 0.29 7.54 6.22 1.11 12.47 11.26 19.95 _ [0051] While the invention has been described above with reference to specific embodiments thereof, it is apparent that many changes, modifications, and variations can be made without departing from the inventive concept disclosed herein. Accordingly, it is intended to embrace all such changes, modifications, and variations that fall within the spirit and broad scope of the appended claims. All patent applications, patents, and other publications cited herein are incorporated by reference in their entirety.
SUBSTITUTE SHEET (RULE 26)
Claims (20)
1. A liquid composition comprising racecadotril and cyclodextrin.
2. The composition of claim 1, wherein the racecadotril is an RS racemic form or R form.
3. The composition of claim 1, wherein the racecadotril is present in an amount of from about 0.10 grams to about 0.30 grams per 100 ml of the liquid composition.
4. The composition of claim 1, wherein the cyclodextrin is alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, or mixtures thereof.
5. The composition of claim 1, wherein the cyclodextrin is present in an amount of from about 40 wt.% to about 65 wt.% per 100 ml of the liquid composition.
6. The composition of claim 1, further comprising an optional ingredient selected from the group consisting of buffers, preservatives, sweeteners, viscosity modifiers, colors, aromas, flavors, and mixtures thereof.
7. The composition of claim 6, wherein the buffer is a citrate, an acetate, a phosphate, or mixtures thereof.
8. The composition of claim 6, wherein the sweetener is sorbitol, high fructose corn syrup, sucralose, aspartame, saccharine, sucrose, or mixtures thereof.
9. The composition of claim 6, wherein the preservative is sodium benzoate, potassium benzoate, propyl paraben, methyl paraben, butyl paraben, or mixtures thereof.
10. The composition of claim 1, wherein the cyclodextrin is a sulfobutyl ether derivative of .beta.-cyclodextrin.
11. A dosage form comprising the composition of claim 1, wherein the dosage form is a liquid oral dosage form, a soft shell solid dosage form, a hard shell solid dosage form or a tablet dosage form.
12. The composition of claim 1, further comprising a second active ingredient that is a digestive health active ingredient.
13. The composition of claim 1, wherein the composition is delivered orally.
14. The composition of claim 1, wherein the composition is a liquid oral dosage form.
15. A liquid composition comprising racecadotril, wherein the liquid composition has a pH
of from about 3 to about 5 at 25°C.
of from about 3 to about 5 at 25°C.
16. A dosage form comprising the composition of claim 15, wherein the dosage form is a liquid oral dosage form, a soft shell solid dosage form, a hard shell solid dosage form or a tablet dosage form.
17. The composition of claim 15, further comprising a second active ingredient that is a digestive health active ingredient.
18. A liquid composition comprising:
about 0.1 wt.% to about 0.3 wt.% racecadotril;
about 6 wt.% to about 8 wt.% cyclodextrin;
about 16 wt.% to about 19 wt.% sorbitol;
about 45 wt.% to about 55 wt.% high fructose corn syrup;
about 0.1 wt.% to about 0.4 wt.% sodium chloride;
about 0.1 wt.% to about 0.8 wt.% polyethylene glycol;
about 15 wt.% to about 30 wt.% water; and about 0 wt.% to about 0.5 wt.% flavor, wherein each wt.% is based upon 100 ml of the composition.
about 0.1 wt.% to about 0.3 wt.% racecadotril;
about 6 wt.% to about 8 wt.% cyclodextrin;
about 16 wt.% to about 19 wt.% sorbitol;
about 45 wt.% to about 55 wt.% high fructose corn syrup;
about 0.1 wt.% to about 0.4 wt.% sodium chloride;
about 0.1 wt.% to about 0.8 wt.% polyethylene glycol;
about 15 wt.% to about 30 wt.% water; and about 0 wt.% to about 0.5 wt.% flavor, wherein each wt.% is based upon 100 ml of the composition.
19. The composition of claim 18, wherein the cyclodextrin is a sulfobutyl ether derivative of .beta.-cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, or mixtures thereof.
20. A method for treating a subject experiencing diarrhea, comprising the step of orally administering to the subject a composition comprising racecadotril and cyclodextrin.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261665458P | 2012-06-28 | 2012-06-28 | |
| US61/665,458 | 2012-06-28 | ||
| US201361787496P | 2013-03-15 | 2013-03-15 | |
| US61/787,496 | 2013-03-15 | ||
| PCT/US2013/048573 WO2014005021A1 (en) | 2012-06-28 | 2013-06-28 | Racecadotril liquid compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2877724A1 true CA2877724A1 (en) | 2014-01-03 |
Family
ID=48795918
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2877724A Abandoned CA2877724A1 (en) | 2012-06-28 | 2013-06-28 | Racecadotril liquid compositions |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US9084721B2 (en) |
| EP (1) | EP2866802B1 (en) |
| JP (1) | JP6282644B2 (en) |
| KR (1) | KR20150023059A (en) |
| CN (1) | CN104411307B (en) |
| AU (2) | AU2013282402A1 (en) |
| BR (1) | BR112014032801A2 (en) |
| CA (1) | CA2877724A1 (en) |
| CO (1) | CO7160079A2 (en) |
| ES (1) | ES2600628T3 (en) |
| HK (1) | HK1208177A1 (en) |
| IN (1) | IN2014DN11007A (en) |
| MX (1) | MX2015000215A (en) |
| NZ (1) | NZ702930A (en) |
| PH (1) | PH12014502860A1 (en) |
| PT (1) | PT2866802T (en) |
| RU (1) | RU2643325C2 (en) |
| SG (1) | SG11201408565VA (en) |
| WO (1) | WO2014005021A1 (en) |
| ZA (1) | ZA201500620B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101652189B1 (en) | 2008-10-22 | 2016-08-29 | 어레이 바이오파마 인크. | SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS |
| US9114171B2 (en) * | 2012-06-28 | 2015-08-25 | Mcneil-Ppc, Inc. | Racecadotril liquid compositions |
| US9084721B2 (en) | 2012-06-28 | 2015-07-21 | Mcneil-Ppc, Inc. | Racecadotril liquid compositions |
| US9801819B2 (en) | 2012-06-28 | 2017-10-31 | Johnson & Johnson Consumer Inc. | Racecadotril compositions |
| CN104411299B (en) | 2012-06-28 | 2017-11-10 | 麦克内尔-Ppc股份有限公司 | Racecadotril lipid composition |
| MA40859A (en) | 2014-10-29 | 2017-09-05 | Johnson & Johnson Consumer Inc | CADOTRIL PARTICLES |
| CN105125477A (en) * | 2015-08-19 | 2015-12-09 | 黑龙江佰彤儿童药物研究有限公司 | Medicinal preparations containing racecadotril and preparation methods |
| US10045991B2 (en) | 2016-04-04 | 2018-08-14 | Loxo Oncology, Inc. | Methods of treating pediatric cancers |
| CA3019671C (en) | 2016-04-04 | 2024-02-20 | Loxo Oncology, Inc. | Liquid formulations of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide |
| DK3458456T3 (en) | 2016-05-18 | 2020-12-14 | Array Biopharma Inc | PREPARATION OF (S) -N- (5 - ((R) -2- (2,5-DIFLUOROPHENYL) PYRROLIDIN-1-YL) PYRAZOLE [1,5-A] PYRIMIDIN-3-YL) -3-HYDROXYPYRROLIDIN- 1-CARBOXAMID |
| JOP20190092A1 (en) | 2016-10-26 | 2019-04-25 | Array Biopharma Inc | PROCESS FOR THE PREPARATION OF PYRAZOLO[1,5-a]PYRIMIDINES AND SALTS THEREOF |
| KR102195776B1 (en) * | 2017-03-06 | 2020-12-29 | 아테나 파르마쎄티크 에스에이에스 | Pharmaceutical composition containing racecadotril and method for preparing same |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3346123A1 (en) * | 1983-12-21 | 1985-06-27 | Janssen Pharmaceutica, N.V., Beerse | PHARMACEUTICAL PREPARATIONS OF SUBSTANCES MEDICAL OR UNSTABLE IN WATER AND METHOD FOR THE PRODUCTION THEREOF |
| FR2673105B1 (en) * | 1991-02-26 | 1995-01-13 | Bioprojet Soc Civ | NOVEL PHARMACEUTICAL COMPOSITIONS, ESPECIALLY FOR THE TREATMENT OF FUNCTIONAL COLOPATHIES, AND METHODS OF PREPARING COMPOSITIONS AND MEDICAMENTS, ESPECIALLY FOR THE TREATMENT OF THESE CONDITIONS. |
| GB9316580D0 (en) * | 1993-08-10 | 1993-09-29 | Smithkline Beecham Plc | Pharmaceutical composition |
| CN1635884A (en) * | 2000-06-23 | 2005-07-06 | 生物计划公司 | Dry powder formulation comprising racecadotril |
| GB0028575D0 (en) * | 2000-11-23 | 2001-01-10 | Elan Corp Plc | Oral pharmaceutical compositions containing cyclodextrins |
| US7034013B2 (en) * | 2001-03-20 | 2006-04-25 | Cydex, Inc. | Formulations containing propofol and a sulfoalkyl ether cyclodextrin |
| EP1563848A1 (en) * | 2004-02-12 | 2005-08-17 | Bioprojet | New combinations of an anti-emetic agent and an enkephalinase inhibitor |
| MXPA06012777A (en) * | 2004-05-06 | 2007-02-14 | Cydex Inc | Taste-masked formulations containing sertraline and sulfoalkyl ether cyclodextrin. |
| JP2009013140A (en) * | 2007-07-09 | 2009-01-22 | Japan Science & Technology Agency | Aqueous suspension of cyclodextrin inclusion complex and method for producing the same |
| EP2462922A1 (en) * | 2010-12-10 | 2012-06-13 | Bioprojet | New form of administration of enkephalinase inhibitor |
| US9801819B2 (en) | 2012-06-28 | 2017-10-31 | Johnson & Johnson Consumer Inc. | Racecadotril compositions |
| US9084721B2 (en) | 2012-06-28 | 2015-07-21 | Mcneil-Ppc, Inc. | Racecadotril liquid compositions |
| US9114171B2 (en) | 2012-06-28 | 2015-08-25 | Mcneil-Ppc, Inc. | Racecadotril liquid compositions |
-
2013
- 2013-06-28 US US13/929,975 patent/US9084721B2/en active Active
- 2013-06-28 CA CA2877724A patent/CA2877724A1/en not_active Abandoned
- 2013-06-28 RU RU2015102575A patent/RU2643325C2/en active
- 2013-06-28 KR KR20157001957A patent/KR20150023059A/en not_active Application Discontinuation
- 2013-06-28 AU AU2013282402A patent/AU2013282402A1/en not_active Abandoned
- 2013-06-28 ES ES13737926.9T patent/ES2600628T3/en active Active
- 2013-06-28 BR BR112014032801A patent/BR112014032801A2/en not_active Application Discontinuation
- 2013-06-28 EP EP13737926.9A patent/EP2866802B1/en active Active
- 2013-06-28 NZ NZ702930A patent/NZ702930A/en not_active IP Right Cessation
- 2013-06-28 PT PT137379269T patent/PT2866802T/en unknown
- 2013-06-28 MX MX2015000215A patent/MX2015000215A/en unknown
- 2013-06-28 WO PCT/US2013/048573 patent/WO2014005021A1/en active Application Filing
- 2013-06-28 CN CN201380034639.5A patent/CN104411307B/en not_active Expired - Fee Related
- 2013-06-28 JP JP2015520571A patent/JP6282644B2/en active Active
- 2013-06-28 SG SG11201408565VA patent/SG11201408565VA/en unknown
-
2014
- 2014-12-19 CO CO14279642A patent/CO7160079A2/en unknown
- 2014-12-22 PH PH12014502860A patent/PH12014502860A1/en unknown
- 2014-12-23 IN IN11007DEN2014 patent/IN2014DN11007A/en unknown
-
2015
- 2015-01-27 ZA ZA2015/00620A patent/ZA201500620B/en unknown
- 2015-09-10 HK HK15108864.9A patent/HK1208177A1/en unknown
-
2018
- 2018-04-09 AU AU2018202482A patent/AU2018202482A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| SG11201408565VA (en) | 2015-02-27 |
| US9084721B2 (en) | 2015-07-21 |
| IN2014DN11007A (en) | 2015-09-25 |
| EP2866802B1 (en) | 2016-07-27 |
| CO7160079A2 (en) | 2015-01-15 |
| CN104411307B (en) | 2017-04-26 |
| AU2013282402A1 (en) | 2015-01-22 |
| US20140005261A1 (en) | 2014-01-02 |
| KR20150023059A (en) | 2015-03-04 |
| JP2015522030A (en) | 2015-08-03 |
| ES2600628T3 (en) | 2017-02-10 |
| EP2866802A1 (en) | 2015-05-06 |
| RU2643325C2 (en) | 2018-01-31 |
| RU2015102575A (en) | 2016-08-20 |
| AU2018202482A1 (en) | 2018-04-26 |
| PT2866802T (en) | 2016-09-05 |
| PH12014502860B1 (en) | 2015-02-23 |
| NZ702930A (en) | 2017-05-26 |
| JP6282644B2 (en) | 2018-02-21 |
| CN104411307A (en) | 2015-03-11 |
| PH12014502860A1 (en) | 2015-02-23 |
| ZA201500620B (en) | 2017-09-27 |
| WO2014005021A1 (en) | 2014-01-03 |
| MX2015000215A (en) | 2015-04-10 |
| BR112014032801A2 (en) | 2017-06-27 |
| HK1208177A1 (en) | 2016-02-26 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20180614 |
|
| FZDE | Discontinued |
Effective date: 20200831 |